Oncotarget

Research Papers:

Antineoplastic effects of selective CDK9 inhibition with atuveciclib on cancer stem-like cells in triple-negative breast cancer

Daphne Brisard _, Frank Eckerdt, Lindsey A. Marsh, Gavin T. Blyth, Sarika Jain, Massimo Cristofanilli, Dai Horiuchi and Leonidas C. Platanias

PDF  |  HTML  |  Supplementary Files  |  How to cite  |  Order a Reprint

Oncotarget. 2018; 9:37305-37318. https://doi.org/10.18632/oncotarget.26468

Metrics: PDF 915 views  |   HTML 1559 views  |   ?  


Abstract

Daphne Brisard1,2, Frank Eckerdt1,3, Lindsey A. Marsh1,2, Gavin T. Blyth1,4, Sarika Jain1,4, Massimo Cristofanilli1,4, Dai Horiuchi1,2 and Leonidas C. Platanias1,4,5

1Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois, USA

2Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA

3Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA

4Division of Hematology/Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA

5Department of Medicine, Jesse Brown VA Medical Center, Chicago, Illinois, USA

Correspondence to:

Leonidas C. Platanias, email: l-platanias@northwestern.edu

Keywords: triple-negative breast cancer (TNBC); cancer stem-like cells; CDK9; MYC; atuveciclib

Received: October 23, 2018     Accepted: December 04, 2018     Published: December 18, 2018

ABSTRACT

Treatment options for triple-negative breast cancer (TNBC) are limited due to the lack of efficient targeted therapies, frequently resulting in recurrence and metastatic disease. Accumulating evidence suggests that a small population of cancer stem-like cells (CSLCs) is responsible for tumor recurrence and therapy resistance. Here we investigated the role of cyclin-dependent kinase 9 (CDK9) in TNBC. Using The Cancer Genome Atlas (TCGA) data we found high-CDK9 expression correlates with worse overall survival in TNBC patients. Pharmacologic inhibition of CDK9 with atuveciclib in high-CDK9 expressing TNBC cell lines reduced expression of CDK9 targets MYC and MCL1 and decreased cell proliferation and survival. Importantly, atuveciclib inhibited the growth of mammospheres and reduced the percentage of CD24low/CD44high cells, indicating disruption of breast CSLCs (BCSLCs). Furthermore, atuveciclib impaired 3D invasion of tumorspheres suggesting inhibition of both invasion and metastatic potential. Finally, atuveciclib enhanced the antineoplastic effects of Cisplatin and promoted inhibitory effects on BCSLCs grown as mammospheres. Together, these findings suggest CDK9 as a potential therapeutic target in aggressive forms of CDK9-high TNBC.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 26468